1Department of Pathology, The Ohio State University Medical Center, Columbus, OH 43210, USA.

Abstract

p16(INK4) and RB1 are two potent cell cycle regulators to control the G1/S transition by interacting with CDK4/6, E2F, and D-type cyclins, respectively. Depending on the tumour type, genetic alterations resulting in the functional inactivation have frequently been reported in both genes. By contrast, much less is known regarding the overexpression of these proteins in the tumor cells. In this study, expressions of p16(INK4) RB1, and CDKN2A copy number variances (CNV) in the tumor cells were assessed by immunohistochemistry and fluorescence in situ hybridization (FISH), respectively, in 73 nonsmall cell lung cancer (NSCLC) with known 5-year survivals. The histologic type (P = 0.01), p16(INK4) (P = 0.004), and RB1 (P < 0.001) were predictive of survivals. The CDKN2A CNV (P < 0.05) was also significant when compared to those cases without CNV. Therefore, among the molecular genetic prognostic factors, expressions of RB1 and p16(INK4) in the tumor cells were the most strongly predictive of adverse outcomes in stage I and II nonsquamous NSCLC.

p16INK4 immunohistochemical staining in lung cancer samples. The patterns in tumor cells range from strong (3+) in an adenocarcinoma with acinar differentiation, moderate (2+) in a mixed adenocarcinoma, and weak (1+) in a mixed adenocarcinoma from (a) to (c), respectively. No (0) expression was seen in tumor cells from a large cell neuroendocrine carcinoma (d) and an adenocarcinoma with acinar differentiation (e-f). There is no expression in normal lung tissue (f) or stromal including normal lymphocytes of the the tumor samples (a–e).

RB1 immunohistochemical staining in lung cancer samples. The represesntative patterns of expression range from strong (3+) in a mixed adenocarcinoma (a), a large cell neuroendocrine carcinoma (b), moderate (2+) in a large cell neuroendocrine carcinoma (c), and weak (1+) in an adenocarcinoma with acinar differentiation, respectively, in the nuclei of tumor cells. No (0) expression was seen in tumor cells of an mixed adenocarcinoma (e). However, weak expression (1+) is present in normal lung tissue (f) or stroma.